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WO2024197127A1 - Méthodes de traitement de patients pédiatriques avec de l'upadacitinib - Google Patents

Méthodes de traitement de patients pédiatriques avec de l'upadacitinib Download PDF

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Publication number
WO2024197127A1
WO2024197127A1 PCT/US2024/020877 US2024020877W WO2024197127A1 WO 2024197127 A1 WO2024197127 A1 WO 2024197127A1 US 2024020877 W US2024020877 W US 2024020877W WO 2024197127 A1 WO2024197127 A1 WO 2024197127A1
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WIPO (PCT)
Prior art keywords
upadacitinib
dose
twice daily
administering
pediatric patient
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PCT/US2024/020877
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WO2024197127A9 (fr
Inventor
Mohamed-Eslam F. Mohamed
Cheng Thiam TAN
Henrique D. Teixeira
Alvina D. CHU
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AbbVie Inc
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AbbVie Inc
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Priority to AU2024240383A priority Critical patent/AU2024240383A1/en
Priority to CN202480020936.2A priority patent/CN120957723A/zh
Publication of WO2024197127A1 publication Critical patent/WO2024197127A1/fr
Publication of WO2024197127A9 publication Critical patent/WO2024197127A9/fr
Priority to MX2025011087A priority patent/MX2025011087A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • Upadacitinib is a JAK1 selective inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic spondyloarthritis, and ulcerative colitis in adults, and the treatment of atopic dermatitis in adults and adolescents 12 years of age and older and weighing 40 kg or more.
  • Upadacitinib is also under investigation for use in treating adults having Crohn’s disease, hidradenitis suppurativa and systemic lupus erythematosus.
  • Upadacitinib has not been evaluated for the treatment of pediatric patients under 12 years of age or under 18 years of age and weighing less than 40 kg.
  • the pharmacokinetics, safety, and tolerability of upadacitinib in adults is known, the pharmacokinetics, safety, and tolerability of upadacitinib in pediatric patients under 12 years of age or under 18 year of age and weighing less than 40 kg has not been studied. Because the above identified diseases also occur in pediatric patients, it is desirable in the art to provide safe and efficacious doses of upadacitinib in pediatric patients.
  • the present disclosure provides methods for treating a disease or disorder in a pediatric patient in need thereof with upadacitinib.
  • the diseases and disorders include idiopathic arthritis (pcJIA), systemic juvenile idiopathic arthritis (SJIA), juvenile psoriatic arthritis (JPsA), atopic dermatitis (AD), juvenile ankylosing spondylitis (JAS), juvenile non-radiographic spondyloarthritis -1- WBD (US) 4865-7655-6714v1 (nr-axSpA), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), ulcerative colitis (UC), and Crohn’s disease (CD).
  • pcJIA idiopathic arthritis
  • SJIA systemic juvenile idiopathic arthritis
  • JPsA juvenile psoriatic arthritis
  • AD atopic dermatitis
  • JS juvenile ankylosing spondylitis
  • JS juvenile non-radiographic spondyloarthritis -1- WBD
  • US 4865
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form. [0007] In some embodiments, the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprising administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0017] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0018] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • the pcJIA is rheumatoid factor-positive or rheumatoid factor-negative polyarticular JIA.
  • the pediatric patient has a history of arthritis affecting at least 5 joints within the first 6 months of disease.
  • the pediatric patient does not have a diagnosis of enthesitis-related arthritis (ERA) or juvenile psoriatic arthritis (JPSA).
  • the pediatric patient has: a) 5 or more active joints as defined by the presence of swollen joints not due to deformity; or b) in the absence of swelling, joints with limitation of movement (LOM) plus pain on motion and/or tenderness with palpation, with LOM present in at least three of the active joints.
  • the pediatric patient is receiving a stable dose of ⁇ 20 mg/m 2 of methotrexate for at least 8 weeks before the start of administration.
  • the pediatric patient is receiving a stable dose of oral glucocorticoids no greater than 10 mg/day or 0.2 mg/kg/day, whatever is lower, for at least 1 week before the start of administration.
  • the pediatric patient achieves one or more of: a JIA ACR pediatric 30/50/70/90/100 response, a change from baseline in JADAS10/27/71 responses, low disease activity according to JADAS-based criteria, or remission according to JADAS-based criteria is achieved at 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 48 weeks, or 52 weeks after the first daily administration.
  • the pediatric patient achieves a JIA ACR pediatric 30 response at 12 weeks after the first daily administration.
  • the -4- WBD (US) 4865-7655-6714v1 pediatric patient achieves a JIA ACR pediatric 50 response at 12 weeks after the first daily administration.
  • the pediatric patient achieves a JIA ACR pediatric 70 response at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves a JIA ACR pediatric 90 response at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves a JIA ACR pediatric 100 response at 12 weeks after the first daily administration. [0028] In some embodiments, the pediatric patient achieves a JIA ACR pediatric 30 response at 24 weeks after the first daily administration. In some embodiments, the pediatric patient achieves a JIA ACR pediatric 50 response at 24 weeks after the first daily administration. In some embodiments, the pediatric patient achieves a JIA ACR pediatric 70 response at 24 weeks after the first daily administration.
  • the pediatric patient achieves a JIA ACR pediatric 100 response at 48 weeks after the first daily administration.
  • a method for treating systemic juvenile idiopathic arthritis (SJIA) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 -6- WBD (US) 4865-7655-6714v1 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0041] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0042] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating atopic dermatitis (AD) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient is less than twelve years old and has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient is less than twelve years old and has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering -8- WBD (US) 4865-7655-6714v1 upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient is less than twelve years old and has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • -8- WBD US
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • the pediatric patient achieves an EASI 75 response at 12 weeks after the first daily administration.
  • the pediatric patient achieves an EASI 90 response at 12 weeks after the first daily administration.
  • the pediatric patient achieves an EASI 100 response at 12 weeks after the first daily administration.
  • the pediatric patient achieves an Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1 at 12 weeks after the first daily administration.
  • vIGA-AD Atopic Dermatitis
  • JPsA juvenile psoriatic arthritis
  • the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -10- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -11- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0076] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0077] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating juvenile ankylosing spondylitis comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -12- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -13- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0091] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0092] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating non-radiographic axial spondyloarthritis (nr-axSpA) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -14- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -15- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0106] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0107] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating hidradenitis suppurative (HS) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -16- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -17- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0121] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0122] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating systemic lupus erythematosus (SLE) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -18- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -19- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0136] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0137] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating ulcerative colitis (UC) in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -20- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -21- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0151] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0152] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a method for treating Crohn’s disease in a pediatric patient comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition.
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a solid dosage form.
  • the pediatric patient has a body weight in a range from about 10 kg to less than about 20 kg, the method comprising administering a therapeutically effective amount of upadacitinib, wherein: (i) the upadacitinib is administered twice daily at a dose of 3 mg each (3 mg BID); or -22- WBD (US) 4865-7655-6714v1 (ii) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID).
  • the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 4 mg each (4 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID).
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID); or (ii) the upadacitinib is administered twice daily at a dose of 12 mg each (12 mg BID).
  • the method comprises administering upadacitinib twice daily at a dose of 3 mg each (3 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg each (4 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the method comprises administering upadacitinib twice daily at a dose of 6 mg each (6 mg BID); if the pediatric patient has a body weight in a range from about 20 kg to less than -23- WBD (US) 4865-7655-6714v1 about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg each (8 mg BID); and if the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering upadacitinib twice daily at a dose of 12 mg each (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the twice daily at a dose of 3 mg of upadacitinib, the twice daily at a dose of 4 mg of upadacitinib, the twice daily at a dose of 6 mg of upadacitinib, the twice daily at a dose of 8 mg of upadacitinib, or the twice daily at a dose of 12 mg of upadacitinib is administered to the pediatric patient as a stable oral pharmaceutical solution.
  • the oral solution comprises upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water. [0166] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL. [0167] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering a therapeutically effective amount of upadacitinib to the pediatric patient, wherein: (i) the upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) the upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).
  • the therapeutically effective amount of upadacitinib is administered to the pediatric patient as an extended-release tablet.
  • a stable oral pharmaceutical formulation comprising upadacitinib or a pharmaceutically acceptable salt or solid-state form thereof, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water.
  • the stable oral pharmaceutical formulation comprises the anhydrous free base upadacitinib at a concentration of about 0.5 mg/mL.
  • the stable oral pharmaceutical formulation comprises the anhydrous free base upadacitinib at a concentration of about 1 mg/mL.
  • the buffer is selected from the group consisting of citrate, phosphate, tartrate, succinate, formate, acetate, and combinations thereof.
  • the pH adjusting agent is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.
  • the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propyl paraben, sodium metabisulfite, potassium sorbate, para- hydroxybenzoic acid, para-hydroxybenzoate, and combinations thereof.
  • the sweetener selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.
  • the stable oral pharmaceutical formulation comprises anhydrous free base upadacitinib, citric acid, sodium citrate, sodium benzoate, sucralose, and water.
  • the stable oral pharmaceutical solution has a pH in a range from about 2 to about 5. In some embodiments, the stable oral pharmaceutical solution has a pH in a range from about 3 to about 4.
  • the stable oral pharmaceutical solution has a pH in a range from about 2.5 to about 3.5.
  • FIG.1 is a schematic illustration of a clinical study in pediatric polyarticular course juvenile idiopathic arthritis patients according to a non-limiting embodiment of the disclosure.
  • FIG. 2 is a graphical depiction of mean upadacitinib plasma concentration-time profiles in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIGS. 5A to 5D are graphical depictions of mean upadacitinib plasma concentration-time profiles in pediatric atopic dermatitis patients according to non-limiting embodiments of the disclosure.
  • FIG.6 is a schematic illustration of a clinical study in pediatric polyarticular course juvenile idiopathic arthritis patients according to a non-limiting embodiment of the disclosure.
  • FIG.7 is a schematic illustration of patient disposition in the clinical study of Example 1.
  • FIGS. 8A to 8C are graphical depictions of mean upadacitinib plasma concentration-time profiles in pediatric polyarticular course juvenile idiopathic arthritis patients for various formulations according to non-limiting embodiments of the disclosure. -25- WBD (US) 4865-7655-6714v1 [0187] FIGS.
  • FIG. 9A to 9E are a series of graphical depictions of efficacy of upadacitinib at week 12 according to various measures and stratified by age group in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10A is a graphical depiction of efficacy of upadacitinib over time through week 48 according to JIA ACR response rate in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10A is a graphical depiction of efficacy of upadacitinib over time through week 48 according to JIA ACR response rate in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10B is a graphical depiction of efficacy of upadacitinib over time through week 48 according to JADAS-27 [CRP] response rate in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10C is a graphical depiction of efficacy of upadacitinib over time through week 48 according to mean change in C-CHAQ from baseline in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10B is a graphical depiction of efficacy of upadacitinib over time through week 48 according to JADAS-27 [CRP] response rate in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • FIG. 10C is a graphical depiction of efficacy of upadacitinib over time through week 48 according to mean change in C-CHAQ from baseline in pediatric polyarticular
  • 10D is a graphical depiction of efficacy of upadacitinib over time through week 48 according to mean change in total number of active joints from baseline in pediatric polyarticular course juvenile idiopathic arthritis patients according to non-limiting embodiments of the disclosure.
  • DETAILED DESCRIPTION OF THE DISCLOSURE I. Definitions [0192] Section headings as used in this section and the entire disclosure are not intended to be limiting. [0193] Where a numeric range is recited, each intervening number within the range is explicitly contemplated with the same degree of precision.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated.
  • all recited ratios also include all sub-ratios falling within the broader ratio.
  • the singular forms "a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
  • the term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result).
  • AUC refers to the area under the curve. AUC is the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time.
  • Cmax refers to the plasma concentration of the referent drug at Tmax, expressed herein as ng/mL, produced by the oral ingestion of a single dose, or indicated number of doses, of the dosage form or pharmaceutical composition, such as the dosage forms and compositions of the present disclosure. Unless specifically indicated, Cmax refers to the overall maximum observed concentration.
  • the terms “treating”, “treatment”, and “therapy” and the like, as used herein, are meant to include therapeutic measures for a disease or disorder leading to any clinical desirable or beneficial effect, including but not limited to alleviation or relief of one or more symptoms, regression, slowing or cessation of progression of the disease or disorder.
  • “pediatric patient” refers to a human patient of less than 18 years old.
  • the terms “patient” and “subject” are used interchangeably herein.
  • “Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalic acid, tartaric acid such as mono tartaric acid (e.g., (+) or (-)-tartaric acid or mixtures thereof), amino
  • Upadacitinib has the structure shown below: -27- WBD (US) 4865-7655-6714v1 [0203]
  • the dosage strength of upadacitinib recited in the present application is based on the weight of anhydrous freebase upadacitinib present in the active ingredient delivered to the patient.
  • a dose of "15 mg of upadacitinib” or “UPA 15 MG” refers to the 15 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient.
  • any coformer e.g., solvent or water molecule(s)
  • a solvate or hydrate including hemihydrate
  • counteranions of a pharmaceutically acceptable salt that may also be present in the active ingredient.
  • the administration of "15 mg of upadacitinib” includes the administration of 15.4 mg of crystalline upadacitinib freebase hemihydrate (which includes 1/2 of a water conformer molecule per upadacitinib freebase molecule) which delivers 15 mg of anhydrous freebase upadacitinib to a patient.
  • a dose of "30 mg of upadacitinib” or ““UPA 30 MG” refers to the 30 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient.
  • coformer e.g., solvent or water molecule(s)
  • a solvate or hydrate including hemihydrate
  • counteranions of a pharmaceutically acceptable salt that may also be present in the active ingredient.
  • the administration of "30 mg of upadacitinib” includes the administration of 30.7 mg of crystalline upadacitinib freebase hemihydrate (which includes 1/2 of a water conformer molecule per upadacitinib freebase molecule) which delivers 30 mg of anhydrous freebase upadacitinib to a patient.
  • Upadacitinib can be administered to a human patient by itself or in pharmaceutical composition where it is mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • compositions of the present disclosure may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which -28- WBD (US) 4865-7655-6714v1 can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the pharmaceutical composition is a capsule dosage form.
  • the pharmaceutical composition is a tablet dosage form.
  • tablet is a controlled-release formulation, such as an extended-release tablet dosage form (also referred to herein as a modified release or sustained release formulation Examples of solid dosage forms comprising upadacitinib may be found in WO 2017/066775, which is hereby incorporated by reference in its entirety.
  • the composition is a stable liquid pharmaceutical composition.
  • the stable liquid pharmaceutical composition is a stable oral solution.
  • the stable liquid pharmaceutical composition is a stable oral suspension.
  • Suitable stable liquid pharmaceutical compositions comprise upadacitinib or a pharmaceutically acceptable salt or solid-state form thereof, along with excipients such as buffers, preservatives, sweeteners, flavoring agents, pH adjusting agents, solvents, and the like.
  • the stable liquid pharmaceutical composition is a stable oral pharmaceutical solution comprising upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water.
  • the stable liquid pharmaceutical composition is a stable oral pharmaceutical suspension comprising upadacitinib, a buffer and/or pH adjusting agent, a preservative, a sweetener, and water.
  • the concentration of upadacitinib in the stable liquid pharmaceutical composition may vary. Due to the bitterness of upadacitinib, which is difficult to mask at higher concentrations for palatability (see, e.g., Example 6), it is generally present at about 1 mg/mL or less.
  • the stable pharmaceutical composition is an oral solution comprising: upadacitinib at a concentration in a range from about 0.3 mg/mL to about 1.2 mg/mL, such as from about 0.3 to about 0.7 mg/mL, or from about 0.8 to about 1.2 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL.
  • the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL. -29- WBD (US) 4865-7655-6714v1 [0210] In some embodiments, the oral solution comprises a pH adjusting agent. Suitable pH adjusting agents include acids such as mineral or organic acids. Mineral acids include but are not limited to hydrochloric, sulfuric, and phosphoric acid. As used herein, the term "organic acid” refers to an organic (i.e., carbon-based) compound that is characterized by acidic properties.
  • organic acids are relatively weak acids (i.e., they do not dissociate completely in the presence of water), such as carboxylic acids (-CO2H).
  • the pH adjusting agent is an organic acid.
  • Suitable organic acids include, but are not limited to, benzoic acid, toluic acids, salicylic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alpha-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,
  • the pH adjusting agent is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.
  • the pH adjusting agent is citric acid.
  • the stable liquid pharmaceutical composition comprises a buffer. Suitable buffers include, but are not limited to, citrate, phosphate, tartrate, succinate, glycinate, glycerophosphate, formate, and acetate.
  • the buffer is selected from the group consisting of citrate, phosphate, tartrate, succinate, formate, acetate, and combinations thereof.
  • the buffer is selected from the group consisting of citrate and phosphate.
  • the buffer is sodium citrate.
  • the quantity of pH adjusting agent and/or buffer may vary. Generally, the concentration of each is adjusted to provide a desired pH range of the resulting stable liquid pharmaceutical composition.
  • the stable liquid pharmaceutical composition has a pH in a range from about 2 to about 5, or from about 3 to about 4, or from about 2 to about 3, or from about 4 to about 5, or from about 2.0 to about 2.5, or from about 2.5 to about 3.0, or from about 3.0 to about 3.5, or from about 3.5 to about 4.0, or from about 4.0 to about 4.5, or from about 4.5 to about 5.0, or from about 3.0 to about 3.1, or from about 3.0 to about 3.2, or from about 3.0 to about 3.3, or from about -30- WBD (US) 4865-7655-6714v1 3.1 to about 3.2, or from about 3.1 to about 3.3, or from about 3.1 to about 3.4, or from about 3.1 to about 3.5, or from about 3.2 to about 3.3,
  • the stable liquid pharmaceutical composition has a pH of about 3.0, or about 3.1, or about 3.2.
  • the stable liquid pharmaceutical composition comprises a preservative. Suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, ascorbic acid, potassium sorbate, 4-hydroxybenzoic acid, 4-hydroxybenzoate, methyl paraben, propyl paraben, sodium metabisulfite, and combinations thereof.
  • the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propyl paraben, sodium metabisulfite, potassium sorbate, para-hydroxybenzoic acid, para-hydroxybenzoate, and combinations thereof.
  • the stable liquid pharmaceutical composition comprises a sweetener.
  • the sweetener can be any sweetener or combination of sweeteners, in natural or artificial form, or as a combination of natural and artificial sweeteners.
  • natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, and the like.
  • artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, and the like.
  • the sweetener comprises one or more sugar alcohols.
  • Sugar alcohols are polyols derived from monosaccharides or disaccharides that have a partially or fully hydrogenated form.
  • Sugar alcohols have, for example, about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates).
  • the sweetener is selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.
  • the stable oral pharmaceutical solution comprises one or more flavoring agents. Any flavorful or aromatic substance capable of altering the taste, fragrance, or both of the solution may be utilized. Flavoring agents may be natural or synthetic. Suitable flavoring agents include, but are not limited to, flavor packages imparting flavors such as cherry, orange, lemon, lime, bubblegum, grape, strawberry, mango, and the like.
  • the stable oral pharmaceutical solution comprises a taste modifier.
  • Suitable taste modifiers include, but are not limited to, salts such as sodium chloride, and monoammonium glycyrrhizinate to accentuate sweetness.
  • the stable pharmaceutical composition is an oral solution comprising upadacitinib, citric acid, sodium citrate, sodium benzoate, sweetener, and water. -31- WBD (US) 4865-7655-6714v1
  • the stable pharmaceutical composition comprises citric acid in an amount in a range from about 0.1 to about 1 mg/mL.
  • the stable pharmaceutical composition comprises sodium citrate in an amount in a range from about 0.01 to about 1 mg/mL.
  • the stable pharmaceutical composition comprises sodium benzoate in an amount in a range from about 0.01 to about 0.1 mg/mL.
  • the stable pharmaceutical composition comprises a sweetener in an amount in a range from about 1 to about 50 mg/mL.
  • the stable pharmaceutical composition is an oral solution having the formulation provided in Table 1. Table 1. Formulation of upadacitinib oral solution (1 mg/mL) [0223]
  • the pH of the stable oral solution may vary. In some embodiments, the stable oral solution has a pH in a range from about 2 to about 5. In some embodiments, the stable oral solution has a pH in a range from about 3 to about 4.
  • the stable oral solution has a pH in a range from about 2.5 to about 3.5.
  • IV. Pediatric dosing [0224] In some embodiments, the pediatric patient has an age of less than 18 years. In some embodiments, the pediatric patient has an age of less than 12 years. In some embodiments, the pediatric patient has an age of less than 6 years. In some embodiments, the pediatric patient has an age in a range from about 2 to less than about 6 years, in a range from about 6 to less than about 12 years, or in a range from about 12 to less than about 18 years.
  • the pediatric patient has an age in a range from about 2 to about 18 years, such as about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, or about 18 years of age. In some embodiments, the pediatric patient is two years of age or older. In some embodiments, the pediatric patient has an age in a range from about 2 to less than 12 years old. -32- WBD (US) 4865-7655-6714v1 [0225] In some embodiments, the pediatric patient has a body weight of at least about 10 kg.
  • the pediatric patient has a body weight from about 10 kg to less than about 30 kg, such as from about 20 to less than about 20 kg, or from about 20 to less than about 30 kg. In some embodiments, the pediatric patient has a body weight 30 kg or more. In some embodiments, the pediatric patient has an age in a range from about 2 to less than 12 years old and weighs less than 40 kg. In some embodiments, the pediatric patient has an age of 12 years old or greater and weighs less than 40 kg. [0226] In some embodiments, the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • 3 mg of upadacitinib twice daily 3 mg BID
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL. [0228] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL. [0230] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL.
  • the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL.
  • the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL.
  • the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL.
  • the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL. [0247] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution. [0248] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, such as from about 0.8, 0.9, or about 1.0, to about 1.1 or about 1.2 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.9 mg/mL to about 1.1 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg/mL. [0253] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL, such as from about 0.3, 0.4, or about 0.5, to about 0.6 or about 0.7 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration from about 0.4 mg/mL to about 0.6 mg/mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg/mL.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the maximal concentration achieved (C max ) with the aforementioned dosing may vary depending on e.g., the dose, the weight of the patient, and the individual patient's metabolism of upadacitinib.
  • a mean Cmax for upadacitinib is achieved in a range from about 20 to about 160 ng/mL.
  • a mean Cmax for upadacitinib is achieved in a range from about 25 to about 50 ng/mL, such as from about 25 to about 35, from about 25 to about 33, from about 25 to about 31, from about 25 to about 29, or from about 25 to about 27 ng/mL.
  • a mean Cmax for upadacitinib is achieved in a range from about 40 to about 100 ng/mL, such as from about 40 to about 95, from about 40 to about 90, from about 40 to about 85, from about 40 to about 80, from about 40 to about 75, from about 40 to about 70, from about 40 to about 65, from about 40 to about 60, from about 40 to about 55, from about 40 to about 50, or from about 40 to about 45 ng/mL.
  • a mean Cmax for upadacitinib is achieved in a range from about 45 to about 50 ng/mL, such as from about 45 to about 49, from about 45 to about 48, from about 45 to about 46, or from about 45 to about 46 ng/mL.
  • a mean Cmax for upadacitinib is achieved -36- WBD (US) 4865-7655-6714v1 in a range from about 150 to about 160 ng/mL, such as from about 152 to about 159, from about 153 to about 158, from about 154 to about 156, or from about 154 to about 155 ng/mL.
  • the mean 24-hour exposure achieved (AUC0-24) with the aforementioned dosing may vary, depending on e.g., the dose, the weight of the patient, the fed vs.
  • a mean AUC 0-24 for upadacitinib is achieved in a range from about 200 to about 700 ng ⁇ h/mL.
  • a mean AUC 0-24 for upadacitinib is achieved in a range from about, such as from about 220 to about 270 ng ⁇ h/mL, such as from about 220 to about 265, from about 220 to about 260, from about 220 to about 255, from about 220 to about 250, from about 220 to about 245, from about 220 to about 240, from about 220 to about 235, from about 220 to about 230, or from about 220 to about 225 ng ⁇ h/mL.
  • a mean AUC0-24 for upadacitinib is achieved in a range from about 340 to about 590 ng ⁇ h/mL, such as from about 340 to about 580, from about 340 to about 570, from about 340 to about 560, from about 340 to about 550, from about 340 to about 540, from about 340 to about 530, from about 340 to about 520, from about 340 to about 510, from about 340 to about 500, from about 340 to about 490, from about 340 to about 480, from about 340 to about 470, from about 340 to about 460, from about 340 to about 450, from about 340 to about 440, from about 340 to about 430, from about 340 to about 420, from about 340 to about 410, from about 340 to about 400, from about 340 to about 390, from about
  • a mean AUC0-24 for upadacitinib is achieved in a range from about 570 to about 590 ng ⁇ h/mL, such as from about 570 to about 590, from about 570 to about 588, from about 570 to about 586, from about 570 to about 584, from about 570 to about 582, or from about 570 to about 580 ng ⁇ h/mL.
  • a mean AUC 0-24 for upadacitinib is achieved in a range from about 45 to about 50 ng ⁇ h/mL, such as from about 45 to about 49, about 46 to about 48, or from about 47 to about 48 ng ⁇ h/mL.
  • a mean AUC0-24 for upadacitinib is achieved in a range from about 650 to about 680 ng/mL, such as from about 660 to about 670, or from about 665 to about 670 ng ⁇ h/mL.
  • the disclosed methods generally comprise orally administering the upadacitinib to the patient daily for a period of time. In some embodiments, the administration is continued at the same dose and dosing frequency over a treatment period. The duration of the treatment period may vary.
  • the treatment period may be at least 14 days, at least one month, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, 20 years, 50 years, or more.
  • the treatment period is 12 weeks.
  • the treatment period is 156 weeks. In some embodiments, the treatment period is at least 156 weeks. V.
  • the pediatric patient has polyarticular course juvenile idiopathic arthritis (pcJIA), including rheumatoid factor-positive or rheumatoid factor-negative polyarticular JIA, extended oligoarticular JIA, or systemic JIA with active arthritis and without active systemic features.
  • pcJIA polyarticular course juvenile idiopathic arthritis
  • Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment in JIA, since they are believed to be the least toxic agent in children. They provide symptomatic relief but are not considered to be disease modifying.
  • DMARDs Disease-modifying anti-rheumatic drugs
  • MTX methotrexate
  • sulfasalazine sulfasalazine
  • systemic use of corticosteroids is frequent in all JIA conditions but particularly for JIA is less desirable due to many deleterious effects.
  • Systemic and intra-articular corticosteroids are being used in JIA in conjunction with NSAIDs and DMARDs.
  • Intra-articular (IA) corticosteroid injections are recommended in JIA patients who have active arthritis regardless of the use of additional concomitant therapy.
  • IA steroids are frequently used and often induce prolonged remission in children with oligoarticular JIA.
  • Many potent biologic agents are now available for use in the treatment of JIA and are capable of inducing remission in JIA when used as monotherapy or in combination with MTX or other synthetic DMARDs. However, many patients still do not reach a state of remission or low disease activity with these agents or lose response over time.
  • JAK inhibition is known to inhibit the IL-6 pathway, and IL-6 in turn is known to be involved in the pathogenesis of both RA and juvenile idiopathic arthritis (JIA). See, e.g., Ou et al. Clin Rheumatol.2002, 21:52-6; Mangge et al.
  • upadacitinib could demonstrate an improved benefit/risk profile compared to other less selective JAK inhibitors or other therapeutic strategies for patients with inflammatory diseases.
  • upadacitinib will provide therapeutic benefit in pcJIA.
  • the method generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing (e.g., once or twice daily) will vary based on the weight of the patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a -39- WBD (US) 4865-7655-6714v1 concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • -40- WBD (US) 4865-7655-6714v1 [0283]
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0285] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has a history of arthritis affecting at least 5 joints within the first 6 months of disease (for extended oligoarticular JIA: ⁇ 4 joints during the first 6 months of disease and > 4 joints thereafter), as per International League of Associations for Rheumatology (ILAR) criteria.
  • ILAR International League of Associations for Rheumatology
  • the pediatric patient does not have a diagnosis of enthesitis-related arthritis (ERA) or juvenile psoriatic arthritis (JPSA).
  • the pediatric patient has 5 or more active joints, defined as the presence of swollen joints (not due to deformity) or, in the absence of swelling, joints with limitation of movement (LOM) plus pain on motion and/or tenderness with palpation, with LOM present in at least three of the active joints.
  • the pediatric patient is receiving methotrexate. In such embodiments, the patient should be on a stable dose of ⁇ 20 mg/m 2 for at least 8 weeks before the start of administration.
  • the pediatric patient is receiving oral glucocorticoids.
  • the patient should be on a stable dose (no greater than 10 mg/day or 0.2 mg/kg/day, whatever is lower) for at least 1 week before the start of administration.
  • a stable dose no greater than 10 mg/day or 0.2 mg/kg/day, whatever is lower
  • the patient achieves one or more of a JIA ACR pediatric 30/50/70/90/100 response, a change from baseline in JADAS10/27/71 responses, low disease activity or remission according to JADAS-based criteria.
  • the patient achieves one or more of a JIA ACR pediatric 30/50/70/90/100 response at 12 weeks, 24 weeks, or 48 weeks.
  • the pediatric patient is not using known moderate or strong inhibitors (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, and phenytoin) of drug metabolizing enzymes.
  • moderate or strong inhibitors e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine
  • inducers e.g., carbamazepine, rifampin, phenobarbital, and phenytoin
  • the pediatric patient is not using biologic treatment (etanercept, infliximab, adalimumab, abatacept, golimumab, tocilizumab, ustekinumab, certolizumab pegol, canakinumab, anakinra).
  • biologic treatment etanercept, infliximab, adalimumab, abatacept, golimumab, tocilizumab, ustekinumab, certolizumab pegol, canakinumab, anakinra.
  • the pediatric patient is not using a JAK inhibitor (e.g., commercially available upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], baricitinib [Olumiant®], peficitinib [Smyraf®], abrocitinib [PF-04965842], or filgotinib).
  • a JAK inhibitor e.g., commercially available upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], baricitinib [Olumiant®], peficitinib [Smyraf®], abrocitinib [PF-04965842], or filgotinib.
  • the pediatric patient has moderately to severely active pcJIA.
  • the pediatric patient has had an inadequate response to one or more DM
  • the pediatric patient has had an inadequate response to one or more TNF blockers.
  • Treatment of Pediatric Patients with Systemic Juvenile Idiopathic Arthritis [0301]
  • the pediatric patient has systemic juvenile idiopathic arthritis (SJIA), which may also be referred to as Still's disease or systemic juvenile rheumatoid arthritis.
  • SJIA is officially a subset of juvenile idiopathic arthritis (JIA), although the pathophysiology is most consistent with an autoinflammatory disorder.
  • SJIA affects not only the joints but other parts of the body, including the liver, lungs and heart.
  • SJIA The course of SJIA is highly variable, typically initially manifesting with a several-month period of spiking fevers and rash, with varying degrees of arthralgia and arthritis.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs biologic and nonbiologic disease-modifying antirheumatic drugs
  • JAK inhibition is known to inhibit the IL-6 pathway, and IL-6 in turn is known to be involved in the pathogenesis of both RA and juvenile idiopathic arthritis (JIA). See, e.g., Ou et al. Clin Rheumatol.2002, 21:52-6; Mangge et al. Arthritis Rheum.1995, 38(2):211-20; and Mellins et al. Nat Rev Rheumatol.2011, 7(7):416-26.
  • inhibition of the JAK1 subtype blocks the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, and IL-15, which are known contributors to inflammatory disorders.
  • IL interleukin
  • upadacitinib offers the potential for effective treatment of inflammatory or autoimmune disorders. Without wishing to be bound by any particular theory, it is believed that, based on the differentiated selectivity profile for JAK inhibition, upadacitinib could demonstrate an improved benefit/risk profile compared to other less selective JAK inhibitors or other therapeutic strategies for patients with inflammatory diseases. In particular, it is believed that upadacitinib will provide therapeutic benefit in SJIA. [0303] Pediatric doses achieving exposures consistent with efficacy in adult patients are disclosed herein as described above (i.e., based on body weight).
  • a method of treating SJIA in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing (e.g., once or twice daily) will vary based on the weight of the patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and -44- WBD (US) 4865-7655-6714v1 the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0312] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0313] In some embodiments, the pediatric patient has moderately to severely active sJIA. [0314] In some embodiments, the pediatric patient has had an inadequate response to one or more DMARDs. [0315] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers. VII. Treatment of Pediatric Patients with Atopic Dermatitis [0316] In some embodiments, the pediatric patient has Atopic Dermatitis (AD; also known as atopic eczema).
  • AD also known as atopic eczema
  • AD is an inflammatory, pruritic, chronic or chronically relapsing skin disease. Common clinical characteristics include erythema, edema, xerosis, erosions/excoriations, oozing and crusting, and lichenification, but they vary by patient age and chronicity of lesions. Pruritus is a hallmark of the condition that is responsible for much of the disease burden borne by patients and their families (Williams, N. Engl. J. Med.2005, 352(22):2314-24). AD is one of the most common skin diseases which affects up to 20% of children.
  • AD Alzheimer's disease
  • a method of treating AD in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of AD in an adult patient.
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution -46- WBD (US) 4865-7655-6714v1 comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is less than twelve years old and has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight -47- WBD (US) 4865-7655-6714v1 of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient is twelve years of age or older and has a body weight of less than about 40 kg, the method comprises administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient is twelve years of age or older and has a body weight of less than about 40 kg
  • the method comprises administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient achieves one or more of a validated Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1, or an Eczema Area and Severity Index by at least 75% (EASI 75), 90% (EASI 90) or 100% (EASI 100).
  • the pediatric patient achieves one or more of a validated Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1, or an Eczema Area and Severity Index by at least 75% (EASI 75), 90% (EASI 90) or 100% (EASI 100) is achieved at 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 48 weeks, or 52 weeks after the first daily administration. In some embodiments, the pediatric patient achieves an Eczema Area and Severity Index 75 at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves an Eczema Area and Severity Index 90 at 12 weeks after the first daily administration.
  • vIGA-AD Human Investigator's Global Assessment scale for Atopic Dermatitis
  • the pediatric patient achieves an Eczema Area and Severity Index 100 at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves an Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1 at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves an Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 at 12 weeks after the first daily administration. In some embodiments, the pediatric patient achieves an Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 1 at 12 weeks after the first daily administration. [0330] In some embodiments, the pediatric patient has severe AD.
  • the pediatric patient has moderately to severely active pcJIA. -48- WBD (US) 4865-7655-6714v1 [0332] In some embodiments, the pediatric patient has had an inadequate response to one or more TCS. [0333] In some embodiments, the pediatric patient has had an inadequate response to one or more biologic therapy. VIII. Treatment of Pediatric Patients with Juvenile Psoriatic Arthritis [0334] In some embodiments, the pediatric patient has juvenile psoriatic arthritis (JPsA). JPsA is a chronic systemic inflammatory disease classified as a sub-type of spondyloarthritis (SpA) and characterized by the association of arthritis and psoriasis.
  • SpA spondyloarthritis
  • JPsA The course of JPsA is usually characterized by flares and remissions. Left untreated, patients with JPsA can have persistent inflammation, progressive joint damage, disability, and a reduced life expectancy.
  • Initial treatment of the musculoskeletal symptoms is composed of nonsteroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections, while topical therapies are used for the initial treatment of psoriasis.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • topical therapies are used for the initial treatment of psoriasis.
  • non-biologic DMARDs non-biologic DMARDs
  • MTX methotrexate
  • LEF leflunomide
  • SSZ sulfasalazine
  • TNF anti-tumor necrosis factor
  • Other biologic therapies e.g., IL-12 /23 or IL-17 inhibitors
  • IL-12 /23 or IL-17 inhibitors are also recommended as alternatives to anti-TNF inhibitors in selected PsA subjects. See, e.g., Gossec et al., Ann Rheum Dis.
  • JPsA juvenile psoriatic arthritis
  • the method generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of JPsA in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and -50- WBD (US) 4865-7655-6714v1 the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0347] In some embodiments, the pediatric patient has moderately to severely active JPsA. [0348] In some embodiments, the pediatric patient has had an inadequate response to one or more DMARDs. [0349] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers.
  • JAS juvenile ankylosing spondylitis
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has had an inadequate response to one or more DMARDs. [0366] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers.
  • X. Treatment of Pediatric Patients with Non-Radiographic Axial Spondyloarthritis [0367] In some embodiments, the pediatric patient has non-radiographic axial spondyloarthritis (nr- axSpA). Nr-axSpA is a chronic, inflammatory rheumatic disease primarily affecting the axial skeleton, characterized by chronic back pain (including nocturnal back pain), morning stiffness, enthesitis, peripheral arthritis, and extra-articular manifestations.
  • nr-axSpA a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above.
  • the method generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of nr-axSpA in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 -55- WBD (US) 4865-7655-6714v1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • -56- WBD (US) 4865-7655-6714v1 the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0380] In some embodiments, the pediatric patient has moderately to severely active nr-axSpA. [0381] In some embodiments, the pediatric patient has had an inadequate response to one or more DMARDs. [0382] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers. XI.
  • the pediatric patient has hidradenitis suppurative (HS).
  • HS is a debilitating skin disorder of the apocrine glands (sweat glands found on certain parts of the body) and hair follicles in which swollen, painful, chronically inflamed lesions or lumps develop.
  • HS is confined to areas of the body that contain apocrine glands, such as axillae, areola of the nipple, groin, perineum, circumanal, and periumbilical regions. It is speculated that immunological abnormalities of the hair follicle play a role in the etiology of this disease.
  • HS is a recurring or chronic inflammatory condition affecting particularly young adults, with an average age of onset of 23 years. This poorly understood disease is believed to be under-reported by those who suffer from it, but it is estimated to affect approximately 1% of the general population in the West, with females affected 2 to 5 times more commonly than males (Naldi, L. Epidemiology. In: Hidradenitis Suppurativa; Jemec et al., ed; Heidelberg: Springer.2006). [0384] HS is characterized by recurrent inflamed nodules, abscesses, and fistulas, and occurs when apocrine gland outlets become blocked by perspiration or are unable to drain normally because of incomplete gland development.
  • HS moderate to severe HS
  • Current therapies for moderate to severe HS include short- or long-term oral or topical antibiotics, retinoids, intralesional steroids, oral steroids, immunosuppressive agents such as cyclosporine or methotrexate, radiation, laser therapy and tumor necrosis factor- ⁇ (TNF- ⁇ ) antagonist adalimumab.
  • adalimumab is the only approved treatment for HS, and other TNF antagonists, such as etanercept, have failed to show improvement of HS over a 24-week treatment period (Adams et al., Arch Dermatol.146(5): 501-504, 2010). Given the limited success of treatments for HS and the debilitating nature of this disease, there is a pressing need for an effective treatment.
  • a method of treating HS in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of HS in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • -58- WBD (US) 4865-7655-6714v1 the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the -59- WBD (US) 4865-7655-6714v1 method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has moderate to severe HS. [0397] In some embodiments, the pediatric patient has had an inadequate response to one or more DMARDs. [0398] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers. XII.
  • the pediatric patient has systemic lupus erythematosus (SLE).
  • SLE is an autoimmune disease characterized by antibodies to nuclear and cytoplasmic antigens, multisystem inflammation, protean clinical manifestations, and a relapsing and remitting course. SLE causes widespread inflammation and tissue damage in the affected organs, which may include joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms of SLE vary depending on the affected organs, but may include fatigue, skin rashes, fevers, and pain or swelling in the joints.
  • a method of treating SLE in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above generally comprises administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing (e.g., once or twice daily) will vary based on the weight of the patient.
  • -60- WBD (US) 4865-7655-6714v1 [0402]
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of SLE in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0411] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has moderately to severely active SLE.
  • the pediatric patient has had an inadequate response to one or more DMARDs.
  • the pediatric patient has had an inadequate response to one or more TNF blockers.
  • UC ulcerative colitis
  • IBD idiopathic inflammatory bowel disease
  • UC ulcerative colitis
  • US -62- WBD
  • the clinical course is marked by exacerbation and remission.
  • UC patients significant unmet therapeutic needs remain. Accordingly, it is desirable in the art to provide pediatric patients with safe, well tolerated, and efficacious therapies for treatment of UC.
  • Pediatric doses achieving exposures consistent with efficacy in adult patients are disclosed herein as described above (i.e., based on body weight).
  • a method of treating UC in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above involves treating the pediatric patient suffering from UC by administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing (e.g., once or twice daily) will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of UC in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg -63- WBD (US) 4865-7655-6714v1 BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 12 mg dose is provided BID as about 24 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0426] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet.
  • the pediatric patient has moderately to severely active UC. -64- WBD (US) 4865-7655-6714v1
  • the pediatric patient has had an inadequate response to one or more DMARDs.
  • the pediatric patient has had an inadequate response to one or more TNF blocker.
  • XIV. Treatment of Pediatric Patients with Crohn’s Disease [0429] In some embodiments, the pediatric patient has Crohn’s disease (CD).
  • CD is one of the two primary forms of idiopathic inflammatory bowel disease (IBD).
  • IBD idiopathic inflammatory bowel disease
  • CD is characterized by significant morbidity including abdominal pain, diarrhea, weight loss/malnutrition, fatigue and a progressive nature that leads to complications such as fistulas, strictures and abscesses.
  • Approximately 80% of patients diagnosed with CD will require at least 1 surgery related to the disease at some point in time (Munkholm P, Langholz E, Davidsen M, et al. Gastroenterology.1993, 105(6):1716-23).
  • significant unmet therapeutic needs remain. Accordingly, it is desirable in the art to provide pediatric patients with safe, well tolerated, and efficacious therapies for treatment of CD.
  • a method of treating UC in a pediatric patient utilizing pediatric dosing based on body weight as disclosed herein above involves treating the pediatric patient suffering from UC by administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or an extended-release tablet.
  • the amount of upadacitinib administered, the oral dose form, and the frequency of dosing will vary based on the weight of the patient.
  • the pediatric dosing based on body weight provides exposures consistent with efficacy for the treatment of UC in an adult patient.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 3 mg dose is provided BID as about 3 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 3 mg dose is provided BID as about 6 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 10 to less than about 20 kg, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a -65- WBD (US) 4865-7655-6714v1 concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 4 mg dose is provided BID as about 4 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 4 mg dose is provided BID as about 8 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight in a range from about 20 to less than about 30 kg, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 6 mg dose is provided BID as about 6 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 6 mg dose is provided BID as about 12 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 8 mg dose is provided BID as about 8 mL of the about 1 mg/mL solution.
  • the oral solution comprises upadacitinib at a concentration of about 0.5 mg/mL and the 8 mg dose is provided BID as about 16 mL of the about 0.5 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.
  • the oral solution comprises upadacitinib at a concentration of about 1 mg/mL, and the 12 mg dose is provided BID as about 12 mL of the about 1 mg/mL solution.
  • the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 15 mg of upadacitinib once daily (15 mg QD) as an extended-release tablet. In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprising administering 30 mg of upadacitinib once daily (30 mg QD) as an extended-release tablet. [0441] In some embodiments, the pediatric patient has moderately to severely active CD. [0442] In some embodiments, the pediatric patient has had an inadequate response to one or more DMARDs. [0443] In some embodiments, the pediatric patient has had an inadequate response to one or more TNF blockers.
  • Part 2 Subjects who completed Part 1 and were benefiting from study drug with no ongoing adverse events of special interest or serious adverse events, based on investigator's clinical judgment and with subject/family's agreement, had the option to enroll in Part 2 to receive open-label upadacitinib.
  • Part 2 was an open- -67- WBD (US) 4865-7655-6714v1 label, long-term extension to evaluate long-term safety and tolerability of upadacitinib.
  • Subjects in Part 2 received open-label upadacitinib at the equivalent of the Low Dose level per body weight category.
  • Week 156 if the investigator believed the subject was still benefiting from treatment, they had an option to continue treatment until the end of the study.
  • Part 3 was an additional safety cohort.
  • This additional safety cohort enrolling approximately 70 subjects from all age groups (2 to ⁇ 18 years) was added to evaluate long-term safety and tolerability of upadacitinib without intensive pharmacokinetic sample collection.
  • Part 3 was open to age groups in which Part 1 enrollment was completed. Subjects in Part 3 received open-label upadacitinib at the equivalent of the Low Dose level per body weight category, and, after the baseline and screening visits, followed an identical visit schedule as subjects in Part 2, without intensive pharmacokinetic sampling. Doses were adjusted during the study for any of the body weight categories after review of results from the subjects who completed Study Part 1.
  • Eligibility Criteria • Male or female subjects, ages 2 to less than 18 years, and total body weight of 10 kg or higher at the time of Screening.
  • Prohibited Medications and Therapy In addition to the medications listed in the eligibility criteria, the following was NOT allowed: ⁇ Prior use of biologic treatment must have been discontinued prior to Study Day 1 (etanercept, 4 weeks; infliximab, adalimumab or abatacept, 8 weeks; golimumab, 10 weeks; tocilizumab, ustekinumab, and certolizumab pegol, 12 weeks; canakinumab, 10 weeks; anakinra, 1 week) and is also prohibited during the study. Note: If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
  • Immunosuppressant medications must have been discontinued at least 30 days or 5-half-lives prior to study drug administration through the end of the study.
  • Known current use of moderate or strong inhibitors e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine
  • inducers e.g., carbamazepine, rifampin, phenobarbital, and phenytoin
  • NSAIDs non-steroidal anti-inflammatory drugs
  • glucocorticoids ⁇ 0.2 mg/kg/day prednisone; daily maximum, 10 mg
  • methotrexate [MTX]; ⁇ 20 mg/m 2 body surface area/week
  • the study drug was upadacitinib in the following formats and doses: 7.5 mg tablet, oral; 15 mg tablet, oral; 30 mg tablet, oral; 1 mg/mL solution, oral; 0.5 mg/mL solution, oral. In Part 1, the dose was administered according to three body weight categories.
  • Subjects were categorized based on age group, and the dose administered for seven consecutive days will be based on three different body weight categories per dose level shown in Table 2.
  • the doses evaluated in this study were predicted to provide comparable upadacitinib plasma exposures in each body weight category to those provided by 15 mg QD and 30 mg QD using the extended-release formulation in adult RA subjects.
  • Doses were selected based on population pharmacokinetic analysis of upadacitinib in healthy adults and in adult subjects with RA, and pharmacokinetic simulations across the different body weight categories assuming allometric (weight-based) scaling of upadacitinib pharmacokinetic parameters (volume of distribution and clearance parameters).
  • the doses selected for this study account for the difference in oral bioavailability between the extended-release tablet formulation and the oral solution.
  • the median (90% prediction interval) upadacitinib average plasma exposures over a dosing interval are 15.1 ng/mL (8.96 ng/mL to 32.7 ng/mL) for 15 mg QD and 30.0 ng/mL (18.1 ng/mL to 63.8 ng/mL) for 30 mg QD using the extended-release formulation in -71- WBD (US) 4865-7655-6714v1 adult RA patients; similar exposures were predicted to be achieved in pediatric patients by the low and high doses, respectively, within each body weight category based on pharmacokinetic simulations (Table 2).
  • blood samples for upadacitinib pharmacokinetics were collected prior to -72- WBD (US) 4865-7655-6714v1 dosing and at 1 hour and 2 hours after dosing from subjects at an unscheduled visit that was 4-6 weeks after the subject's dose adjustment visit.
  • blood samples for clinical laboratory testing were also collected.
  • Part 2 [0455] To evaluate the long-term safety and tolerability of upadacitinib in pediatric subjects with pcJIA who completed Part 1. To evaluate descriptive efficacy of upadacitinib in pcJIA. Part 3: [0456] To evaluate the long-term safety and tolerability of upadacitinib in pediatric subjects with pcJIA. To evaluate descriptive efficacy of upadacitinib in pcJIA.
  • Safety Endpoints included incidence of Treatment Emergent Adverse Events (TEAEs), physical examination results, change in vital sign measurements, and clinical laboratory testing (hematology and chemistry) as measures of safety and tolerability for the entire study duration.
  • TEAEs Treatment Emergent Adverse Events
  • physical examination results change in vital sign measurements
  • clinical laboratory testing hematology and chemistry
  • Pharmacokinetic Endpoints [0459] For Part 1, the values for the pharmacokinetic parameters of upadacitinib including C max , time to maximum observed plasma concentration (Tmax), area under the plasma concentration versus time curve during a dosing interval (AUCtau) on Day 7, apparent oral clearance at steady state (CL/F), and -73- WBD (US) 4865-7655-6714v1 half-life were determined using non-compartmental methods.
  • Efficacy Endpoints were used to determine JIA American College of Rheumatology (ACR) response and Juvenile Arthritis Disease Activity Score (JADAS) were collected: • Total number of active joints defined as: • joints with swelling not due to deformity, OR • joints with limitation of movement [LOM] with pain, tenderness or both • Number of joints with LOM • Childhood Health Assessment Questionnaire (C-HAQ) • Physician's Global Assessment of Disease Activity (visual analog scale [VAS]) • Patient's/Caregiver's Global Assessment of Overall Well Being (VAS) • Erythrocyte sedimentation rate (ESR) • C-reactive protein (CRP) [0461] Based on these parameters, the following composite efficacy endpoints were evaluated: • JIA ACR pediatric 30/50/70/90/100 responses • Change from Baseline in JADAS10/27/71 responses, as well as JADAS-based criteria for low disease activity and remission (if deemed useful and appropriate).
  • the low and high doses were selected to provide comparable plasma exposures in pediatrics to 15 mg and 30 mg QD doses of ER tablet formulation in adults, respectively.
  • Patients received bodyweight-based upadacitinib doses either as twice-daily (BID) immediate-release (IR) oral solution or QD extended-release (ER) tablet -74- WBD (US) 4865-7655-6714v1 formulation.
  • BID bodyweight-based upadacitinib doses either as twice-daily
  • IR immediate-release
  • ER QD extended-release
  • US 4865-7655-6714v1 formulation.
  • Pharmacokinetic assessment was performed at steady state on Study Day 7, after which all patients might continue the study with low dose. Results [0464] A summary of the demographics of the enrolled subjects is provided in Table 3. Pharmacokinetic results from 49 patients with evaluable drug concentrations on Study Day 7 were reported.
  • the geometric mean upadacitinib maximum plasma concentration (C max ) and AUC0-24 at steady state were 35.1 ng/mL and 269 ng ⁇ h/mL, respectively.
  • the geometric mean upadacitinib Cmax and AUC0-24 were 69.8 ng/mL and 553 ng ⁇ h/mL, respectively.
  • the geometric mean upadacitinib C max and AUC 0-24 were 51.0 ng/mL and 346 ng ⁇ h/mL, respectively.
  • the geometric mean upadacitinib Cmax and AUC0-24 were 46.6 ng/mL and 369 ng ⁇ h/mL, respectively.
  • the median time to maximum upadacitinib concentration was approximately 3 hours and 1 hour; and the harmonic mean functional half-life was approximately 5 hours and 2 hours for the QD ER tablet and the BID IR solution regimens, respectively.
  • Upadacitinib apparent oral clearance increased in pcJIA patients with increasing bodyweight.
  • the mean upadacitinib plasma concentration- time profiles of each group are presented by dosing regimen in FIG.2.
  • Example 3 Safety and Efficacy of Upadacitinib for Pediatric Patients with Polyarticular Course Juvenile Idiopathic Arthritis: An Interim Analysis of an Open-label, Phase 1 Trial (Analysis of Interim Results of Example 1 through Week 12) Objective [0470] The objective of this study was to evaluate the safety and efficacy of upadacitinib in pediatric patients with pcJIA by age groups.
  • Upadacitinib was administered based on body weight with either BID oral solution or QD extended-release tablet. The low and high doses were selected to provide comparable plasma exposure in pediatric patients to 15 mg and 30 mg QD doses in adults, respectively.
  • PK was evaluated on Day 7 post first dose. Safety was evaluated throughout the study. Exploratory efficacy parameters were collected at specified timepoints.
  • Example 5 Upadacitinib for the Treatment of Severe Atopic Dermatitis in Pediatric Subjects
  • This study was an open-label, multiple-dose phase 1 study to evaluate the pharmacokinetic (PK), safety, and tolerability of upadacitinib in pediatric subjects with severe atopic dermatitis (AD), which remains ongoing.
  • Study Design A schematic of the study design is provided in FIG.4. With reference to FIG.4, the study consisted of two parts.
  • Part 1 was a multiple-dose, open-label, multiple-cohort study that consisted of two sequential multiple-ascending dose groups (Low Dose and High Dose levels) in the two age groups.
  • Upadacitinib dose was administered based on subject's body weight according to pre-defined body weight categories per dose level with at least 4 subjects in each body weight category (Table 5).
  • the objectives of Part 1 were to evaluate the pharmacokinetics, -78- WBD (US) 4865-7655-6714v1 activity, safety, and tolerability of multiple doses of upadacitinib in pediatric subjects with severe atopic dermatitis and to evaluate the palatability of upadacitinib oral solution in pediatric subjects.
  • EASI Eczema Area Severity Index
  • TCS topical corticosteroids
  • TCI topical calcineurin inhibitor
  • FIGS.5A, 5B, 5C, and 5D and Table 9 A summary of upadacitinib PK parameters on Day 7 are provided in FIGS.5A, 5B, 5C, and 5D and Table 9.
  • FIGS.5A, 5B, 5C, and 5D and Table 9 A summary of upadacitinib PK parameters on Day 7 are provided in FIGS.5A, 5B, 5C, and 5D and Table 9.
  • a validated Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1 (with at least two grades of reduction from baseline) at Week 12 was achieved by 9/27 subjects (33.3%) in the overall population across cohorts as of the data cutoff (Table 10), signifying achievement of clear or almost clear skin. Notably, activity was observed in the overall population despite 10 subjects in Cohorts 1, 2, and 3 requiring a dose increase to adequately reach the target upadacitinib plasma exposure.
  • Change from baseline of the Eczema Area and Severity Index by at least 75% (EASI 75) at Week 12 was achieved by 19/27 subjects (70.4%) for the overall population across cohorts as of the data cutoff (Table 11).
  • EASI 75 -81- WBD US
  • EASI 75, vIGA-AD 0/1 and percent change from baseline of the EASI score in these subjects were consistent with those in the overall population at respective timepoints.
  • response rates as measured by EASI75 and vIGA-AD score of 0 or 1 numerically improved 12 weeks after the dose increase.
  • Upadacitinib has good solubility at low pH (shown in Table 13).
  • low pH buffers such as citrate, phosphate, tartrate, and formate are suitable to prepare the oral solution.
  • Buffers with higher pH ranges such as succinate and acetate are also suitable (refer to Example 7) but will result in an oral suspension.
  • Citrate buffer was selected because it has favorable pKa ( ⁇ 3.1), which is close to the final pH of the oral solution. Accordingly, a formulation was developed based on the solubility of upadacitinib in liquid with citric acid and sodium citrate added to completely dissolve upadacitinib. [0493]
  • Upadacitinib has strong bitterness above concentrations of 0.1 mg/mL.
  • An acceptable and palatable formulation has a bitter intensity below 1.0.
  • a sweetener, taste masking or modifier agent, and flavoring agent can mitigate the bitter taste of upadacitinib.
  • Sweeteners or combinations of sweeteners such as acesulfame potassium, sodium saccharin, sucralose, neotame, sucrose, maltitol, and xylitol are suitable for this oral solution.
  • Taste modifiers such as sodium chloride, citric acid and monoammonium glycyrrhinizate are also suitable for this oral solution.
  • Flavoring agents such as cherry, orange, bubblegum, strawberry, and mango can enhance the acceptability of the formulation.
  • Upadacitinib oral solution contains water and sweetener that are potential causes of microbial growth. Upadacitinib oral solution is also a multi-dose formulation. Hence preservative is added into the formulation to prevent microbial proliferation. Preservatives such as sodium benzoate and propyl paraben are suitable based on the final pH of the oral solution. Other preservatives such as sodium metabisulfite, benzoic acid, para-hydroxybenzoate, potassium sorbate and para-hydroxybenzoic acid can also be used based on the final pH of the oral solution or suspension. [0495] The upadacitinib 1 mg/mL oral solution C contained citric acid, sodium citrate, sucralose, sodium benzoate, and water.
  • the 1 mg/mL oral solution C was clear and colorless to light yellow.
  • the composition of certain 1 mg/mL and 0.5 mg/mL oral solutions is shown in Table 14.
  • Table 14 Compositions of proposed upadacitinib oral solutions Example 7.
  • Upadacitinib immediate release or extended-release liquid formulation (suspension) [0496] An immediate release oral suspension is prepared to accommodate higher dosage strength or higher pH.
  • the buffers, preservatives, and sweeteners listed in Example 6 can be applied in this formulation.
  • an extended-release liquid formulation is prepared to provide extended release of upadacitinib for once-daily administration using a release rate modifier, such as an ion exchange resin.
  • the liquid dosage forms comprise an upadacitinib-ion exchange resin complex.
  • the upadacitinib-ion exchange resin complex comprises upadacitinib or a pharmaceutically acceptable salt thereof bound to an ion exchange resin.
  • Suitable ion exchange resins include, but are not limited to, a sulfonated copolymer comprising styrene and divinylbenzene.
  • the mobile, or exchangeable, cation is sodium.
  • Example 8 Safety and Efficacy of Upadacitinib for Pediatric Patients with Polyarticular Course Juvenile Idiopathic Arthritis: An Interim Analysis of an Open-label, Phase 1 Trial (Analysis of Interim Results of Example 1 through Week 48) [0497] This Example provides additional data through week 48 for the study described in Example 1. Objective [0498] The objective of this study was to evaluate the pharmacokinetics, efficacy, and safety of upadacitinib in pediatric patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).
  • a summary of the pharmacokinetic parameters of upadacitinib at steady state (i.e., on Day 7) after administration of upadacitinib in patients enrolled in Part 1 is provided in Table 17.
  • 13 patients in Group 3 and 12 patients in Group 4 received revised doses, and all other patients received the original doses.
  • Upadacitinib Cmax -92- WBD (US) 4865-7655-6714v1 was reached within approximately 3 hours and 1 hour following the administration of the ER tablet and the IR oral solution formulations, respectively.
  • Upadacitinib functional t1/2 was approximately 5 hours within a QD dosing interval for the ER tablet and 2 hours within a BID dosing interval for the IR solution.
  • Table 17. Geometric Mean (Mean, % CV) Pharmacokinetic Parameters of Upadacitinib by Study Group and Dosing Regimen (Part 1) AUC, area under the plasma concentration-time curve from time 0 to 24 hr (AUC 0-24 ) or over a dose interval (AUC tau ); BID, twice daily; C max , maximal plasma concentration; CL ss /F, apparent oral clearance at steady state; CL ss /F_adjusted, CL ss /F adjusted for bioavailability; n, number of patients; QD, once daily; T max , time to maximal plasma concentration; functional t 1/2 , functional half-life.
  • the two younger age groups (2 to ⁇ 6 years and 6 to ⁇ 12 years) had similar improvements in JIA ACR responses, and the oldest age group (12 to ⁇ 18 years) had numerically lower rates of JIA ACR responses compared to the younger age groups without statistical significance.
  • Response to upadacitinib was rapid, with 61.2% of patients achieving JIA ACR 30 as early as Week 1.
  • JIA ACR responses continued to improve at Week 24 and were generally maintained through Week 48 (FIG. 10A).
  • Additional key efficacy measurements including C-HAQ, total number of active joints, Physician's Global Assessment of Disease Activity (VAS), Patient/Parent Global Assessment of Overall Well Being (VAS), and JADAS-27 CRP, JADAS-27 ESR, ESR, and CRP are summarized in Table 18. Across these efficacy measures at Week 12, improvement from baseline was observed in all age groups and changes from baseline were consistent between the age groups. Changes in JADAS-27 ESR were similar to those for JADAS-27 CRP. Twenty-nine (29) of 50 patients (58%) achieved JADAS-27 CRP ⁇ 3.8 and 16 of 50 patients (32%) achieved JADAS-27 CRP ⁇ 1 at Week 12.
  • the observed upadacitinib pharmacokinetics in pediatric patients with pcJIA for the QD regimen using the ER formulation and the BID regimen using the IR formulation were consistent with the characterized upadacitinib pharmacokinetics in adults for the respective formulations.
  • the original dosing regimen of upadacitinib was selected by leveraging pharmacokinetic data of upadacitinib in adult patients with RA and allometric scaling of clearance and volume of distribution based on body weight, with a goal of achieving upadacitinib exposures in patients with pcJIA similar to the exposures which were shown to be optimal in adult RA patients.
  • the median (5 th , 95 th percentile) upadacitinib area under the plasma concentration-time curve (AUC) at steady state in adult patients with RA in phase 3 trials was 358 (234, 701) and 708 (466, 1332) ng ⁇ h/mL after daily administration of 15 mg and 30 mg ER tablets, respectively.
  • the relative median upadacitinib AUC0–24 within each group in this study ranged from approximately 0.77 -96- WBD (US) 4865-7655-6714v1 to 1.07 (Table 19).
  • Upadacitinib Improvements with upadacitinib were observed across the evaluated age groups, which included patients with pcJIA ages 2 to ⁇ 18 years old, with numerically higher response rates in patients ages 2 to ⁇ 12 years than those 12 to ⁇ 18 years. Notably, most patients in the oldest age group had longer disease duration and prior bDMARDs exposure. In comparison, most patients in the younger age groups had shorter disease duration and no prior bDMARD exposure (Table 16). There were no patients with a history of uveitis and no uveitis events occurred during the study. The safety profile of upadacitinib in pediatric patients with pcJIA was generally consistent with the currently known safety profile of upadacitinib in adults and adolescents with inflammatory conditions.
  • upadacitinib was well tolerated and efficacious in patients with pcJIA across all age groups (age 2 to ⁇ 18 years) with plasma exposures comparable to adult RA patients at the evaluated dosing regimens. No new safety risks were observed in pcJIA patients, and the benefit-risk profile of upadacitinib was assessed as favorable based on the safety and efficacy outcomes of the study to date. -97- WBD (US) 4865-7655-6714v1 Table 19.

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Abstract

La présente invention concerne des méthodes de traitement d'une maladie chez des patients pédiatriques à l'aide de l'inhibiteur sélectif de JAK1, l'upadacitinib. Les maladies et les troubles comprennent l'arthrite idiopathique juvénile polyarticulaire (pcJIA), l'arthrite juvénile idiopathique systémique (sJIA), l'arthrite psoriasique juvénile (JPsA), la dermatite atopique, la spondylarthrite ankylosante juvénile (JAS), la spondylarthrite juvénile non radiographique (nr-axSpA), l'hidradénite suppurée, le lupus érythémateux disséminé, la rectocolite hémorragique et la maladie de Crohn. Les méthodes de traitement consistent généralement à administrer à un patient pédiatrique une quantité thérapeutiquement efficace d'upadacitinib sous la forme d'une composition pharmaceutique liquide stable ou d'une forme de dosage solide, à une dose basée sur le poids corporel du patient.
PCT/US2024/020877 2023-03-22 2024-03-21 Méthodes de traitement de patients pédiatriques avec de l'upadacitinib Pending WO2024197127A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017066775A1 (fr) 2015-10-16 2017-04-20 Abbvie Inc. Procédé de préparation de (3s,4r)-3-éthyl-4-(3h-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroéthyl)pyrrolidine-1-carboxamide et de ses formes à l'état solide
US11365198B2 (en) * 2015-10-16 2022-06-21 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11512092B2 (en) * 2015-10-16 2022-11-29 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11524964B2 (en) * 2015-10-16 2022-12-13 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
WO2024073563A1 (fr) * 2022-09-30 2024-04-04 Abbvie Inc. Méthodes de traitement de l'hidradénite suppurée

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017066775A1 (fr) 2015-10-16 2017-04-20 Abbvie Inc. Procédé de préparation de (3s,4r)-3-éthyl-4-(3h-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroéthyl)pyrrolidine-1-carboxamide et de ses formes à l'état solide
US11365198B2 (en) * 2015-10-16 2022-06-21 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11512092B2 (en) * 2015-10-16 2022-11-29 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
US11524964B2 (en) * 2015-10-16 2022-12-13 Abbvie Inc. Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof
WO2024073563A1 (fr) * 2022-09-30 2024-04-04 Abbvie Inc. Méthodes de traitement de l'hidradénite suppurée

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
ADAMS ET AL., ARCH DERMATOL., vol. 146, no. 5, 2010, pages 501 - 504
ANONYMOUS: "A study to evaluate the Pharmacokiinetics, safety and tolerability of Upadacitinib in Pediatric subjects with Polyarticular Juvenile Idiopathic Arthritis (select-youth)", CLINICALTRIALS.GOV, 9 February 2023 (2023-02-09), pages 1 - 24, XP093175150, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT03725007?tab=history&a=21#version-content-panel> *
ANONYMOUS: "HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RINVOQ safely and effectively. See full prescribing information for RINVOQ. RINVOQ (upadacitinib) extended-release tablets, for oral use Initial U.S. Approval: 2019", FOOD DRUG AGENCY ACCESS DATA WEBSITE, 1 April 2021 (2021-04-01), pages 1 - 62, XP093174282, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211675s003lbl.pdf> *
BEREDA GUDISA: "Pediatrics: pharmacokinetics and dose calculation", JOURNAL OF PEDIATRICS & NEONATAL CARE, vol. 12, no. 2, 18 July 2022 (2022-07-18), pages 96 - 102, XP093174703, Retrieved from the Internet <URL:https://medcraveonline.com/JPNC/JPNC-12-00463.pdf> DOI: 10.15406/jpnc.2022.12.00463 *
COATES ET AL., ARTHRITIS RHEUMATOL., vol. 68, 2016, pages 1060 - 71
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1 October 2023 (2023-10-01), KREKHOVA E ET AL: "Efficiency And Safety Of Upadacitinib In Patients With Juvenile Idiopathic Arthritis Without Systemic Features", XP002811745, Database accession no. EMB-642856590 *
DEODHAR ET AL., ARTHRITIS AND RHEUMATOLOGY, vol. 71, 2019, pages 258 - 270
GOSSEC ET AL., ANN RHEUM DIS., vol. 75, 2016, pages 499 - 510
KREKHOVA E ET AL: "Efficiency And Safety Of Upadacitinib In Patients With Juvenile Idiopathic Arthritis Without Systemic Features", PEDIATRIC RHEUMATOLOGY 20231001 BIOMED CENTRAL LTD. NLD, vol. 21, no. Supplement 2, 1 October 2023 (2023-10-01), ISSN: 1546-0096 *
MALKAWI WEDAD ET AL: "Formulation Challenges and Strategies to Develop Pediatric Dosage Forms", CHILDREN, vol. 9, no. 4, 1 April 2022 (2022-04-01), pages 488, XP093175175, ISSN: 2227-9067, DOI: 10.3390/children9040488 *
MANGGE ET AL., ARTHRITIS RHEUM., vol. 38, no. 2, 1995, pages 211 - 20
MELLINS ET AL., NAT REV RHEUMATOL., vol. 7, no. 7, 2011, pages 416 - 26
MOHAMED MOHAMED-ESLAM F. ET AL: "Exposure-Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended-Release Formulation", CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 107, no. 3, 22 November 2019 (2019-11-22), US, pages 639 - 649, XP055965146, ISSN: 0009-9236, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cpt.1668> DOI: 10.1002/cpt.1668 *
MUNKHOLM PLANGHOLZ EDAVIDSEN M ET AL., GASTROENTEROLOGY, vol. 105, no. 6, 1993, pages 1716 - 23
NALDI, L. EPIDEMIOLOGY ET AL.: "In: Hidradenitis Suppurativa", 2006, SPRINGER
OU ET AL., CLIN RHEUMATOL., vol. 21, 2002, pages 52 - 6
PERROTTA ET AL., J RHEUMATOL., vol. 43, 2016, pages 350 - 5
SABER ET AL., ARTHRITIS RES THERAPY, vol. 12, 2010, pages 94
SANDBORN, DIG DIS, vol. 28, 2010, pages 536 - 42
SAVOLAINEN ET AL., J RHEUMATOL., vol. 30, 2003, pages 2460 - 2644
SIEPER ET AL., ANN. RHEUM. DIS., vol. 73, 2014, pages 95 - 100
SIEPER ET AL., ANN. RHEUM. DIS., vol. 74, 2015, pages 1051 - 1057
SONG ET AL., ANN. RHEUM. DIS., vol. 70, 2011, pages 1108 - 1110
WILLIAMS ET AL.: "Atopic dermatitis: the epidemiology, causes, and prevention of atopic eczema.", 2000, CAMBRIDGE UNIVERSITY PRESS, pages: 41 - 59
WILLIAMS, N., ENGL. J. MED, vol. 352, no. 22, 2005, pages 2314 - 24

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